Prostate Cancer Therapy in Evolution: Time to Rethink and Redirect?

The ASCO updated guidelines on the treatment of metastatic non-castrate prostate cancer penned by Morris and his colleagues1 provide valuable information annotated to the strengths of evidence in recently reported prostate cancer studies. CHAARTED, GETUG-AFU 15, LATITUDE, and STAMPEDE have collectively altered the therapy for men with de novo metastatic hormone-naive prostate cancer from conventional androgen-deprivation therapy (ADT) to combination therapies. The revised guidelines will provide appropriate context and discipline to our decision-making.2-6 The studies themselves provide invaluable insights that suggest overlap between the driver biology of metastatic hormone-naive prostate cancer and that of some metastatic castrate-resistant prostate cancers. A remaining clinical question is, should ADT alone be abandoned altogether, or is there a role for it in selected patients?

The focus of the ASCO expert panel was appropriately centered on the optimal application of the two tested therapeutics: abiraterone (Yonsa, Zytiga) and docetaxel. The authors correctly noted that the significant improvement in all outcomes justifies their use for the treatment of the majority of men with hormone-naive metastatic cancers as initial therapy in combination with luteinizing hormone-releasing hormone (LHRH) agonists. Physicians should now discuss and offer both options to patients with newly diagnosed hormone-naive metastatic prostate cancer who are not frail.

Subject of Much Speculation

There is strong evidence favoring the addition of abiraterone in men irrespective of the volume or number of metastases. In the course of developing the guidelines, the authors exposed two issues that have been the subject of much speculation: the first is the discordance in the findings of CHAARTED and STAMPEDE, which demonstrated benefit for docetaxel, relative to GETUG, which detected no benefit. The strength of data is, according to their interpretation, greatest for men with higher volumes of metastatic cancers. However, citing potential differences in the studies and meta-analyses across data sets, they concluded that observations favor meaningful benefit for docetaxel in all.

A remaining clinical question is, should ADT alone be abandoned altogether, or is there a role for it in selected patients?

— Christopher Logothetis, MD and Eleni Efstathiou, MD, PhD

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Meta-analyses have been recently reported with controversial conclusions. Although post hoc analyses have limitations and must be interpreted with caution, they are “hypothesis-generating” and contextualize observations across studies.7,8 The meta-analysis of outcomes in contemporaneously accrued STAMPEDE treatment with abiraterone and docetaxel suggested equivalence between the two arms with regard to overall survival. Based on this finding, both docetaxel and abiraterone are acceptable treatment options for men with metastatic hormone-naive prostate cancer. The benefits of intervention in the hormone-naive state relative to waiting for the emergence of castrate resistance is also clear in patients able to tolerate such therapies. The findings are supported and further extended to the “nonmetastatic castrate-resistant state” by the SPARTAN study.9

The second issue not addressed by the studies is how best to select between docetaxel and abiraterone in individual patients. This issue was likely untouched due to the absence of direct comparative data. The lack of robust data on the clinical interaction between docetaxel and abiraterone may have critical effects on the overall impact of treatment choice on outcomes. Although speculative, it is reasonable to assume there is an optimal sequence that is patient-specific. These and other limitations of the proposed guidelines must generate sufficient concern to take the steps to urgently address the knowledge gaps.

Remedy for Prostate Cancer Research

The weaknesses of our current research approach are obvious. Although treatment algorithms in many adult common solid tumors are transitioning from prognosis-based to those informed by predictive markers linking driver biology to treatment, this is not yet the case for prostate cancer. The improved understanding of androgen signaling in prostate cancer and its dominant role in progression have yet to result in the development of widely used predictive markers. Several reasons may account for this: a significant majority of patients will derive benefit, serial sampling of metastases is challenging, and patients are often elderly or frail. These often-cited reasons require a remedy if the promise of prostate cancer research will efficiently lead to improved outcomes.

The limitations of the guidelines point to the urgent need to prioritize the development of predictive markers, which will be the foundation of future guidelines.

— Christopher Logothetis, MD and Eleni Efstathiou, MD, PhD

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The priority to be addressed is the development of a categorization of prostate cancer by probability of benefit from androgen-signaling inhibition. Such a classification is the first and necessary step to replace the prevailing “one-size-fits-all” approach. Given the therapeutically relevant heterogeneity over time, informative tissues will need to be harvested contemporaneous to the planned intervention. To achieve this, broadly applicable methods must be developed to obtain tissues from bone-forming metastases or liquid biopsies that reflect the underlying biology with fidelity.10,11 New imaging techniques will provide us the opportunity to detect the emergence of cancer and guide specific therapy if developed as biomarkers with the purpose of linking biology to anatomy. The more precise imaging approaches may be a particularly useful tool to enable the integration of surgery or radiation with systemic therapies.

Foundation of Future Guidelines

Taken together, the limitations of the guidelines point to the urgent need to prioritize the development of predictive markers, which will be the foundation of future guidelines. Longitudinal characterization of patients and their cancer will, most likely, improve outcomes by informing course corrections in anticipation of overt clinical disease progression. This is particularly relevant given that patients receiving active treatment in the STAMPEDE and LATITUDE trials were more often offered alternative therapies than those treated with ADT alone. We can only speculate what the cause of this perplexing finding was and how it impacted outcomes. However, it is clear that an understanding of why this difference occurred, and what its impact on outcomes may be, will assist in establishing future research directions.

Bridging the gap between the benefits in patient populations and the challenge faced by physicians tasked with recommending therapy for individuals has been measurably improved with the newly revised guidelines. Although improved, the challenge of individualizing therapy looms large. In our view, the gap will be minimized by the development of a biologically based, therapeutically relevant classification, and methods to monitor patients throughout the course of their illness. We add our voice to the chorus that champions the importance of such a classification and the predictive markers necessary for its clinical application. Failure to do so condemns us to continue the prevailing approach of conducting research in unselected populations and using empiricism to guide the care of individual patients. ■

DISCLOSURE: Drs. Logothetis and Efstathiou reported no conflicts of interest.

Dr. Logothetis is Director, Department of The David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston. Dr. Efstathiou is Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

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